Sulfonylcarboxamide derivatives, process for their preparation and their use as pharmaceuticals

ABSTRACT

Sulfonylcarboxamide derivatives of formula I, their physiologically acceptable salts and/or physiologically functional derivatives, methods of making these compounds, their use for preparing medicines for the prevention and treatment of hyperlipidemia and arteriosclerotic disorders. The compounds of formula I have the following structure:                    
     in which the radicals are as defined and their physiologically acceptable salts and physiologically functional derivatives are described.

This application claims benefit under 35 U.S.C. §119 of application No.19941540.4-44 filed on Sep. 1, 1999 and application No. 10027611.3 ofJun. 6, 2000 in Germany, which are hereby incorporated by reference.

The invention relates to sulfonylcarboxamide derivatives and theirphysiologically acceptable salts and physiologically functionalderivatives and to their use for preparing medicines for the preventionand treatment of hyperlipidemia and arteriosclerotic disorders.

Sulfonylcarboxamides have already been described In Chemical Abstracts96, 142393m (1982).

In DE 2145686, 2-chloro-5-sulfamylbenzoic acid derivatives have alreadybeen described as lipid-lowering agents.

The invention is based on the object of providing further compoundswhich have a therapeutically utilizable hypolipidemic action. In thiscontext, the object was, in particular, also to provide compounds havingan increased hypolipidemic action compared to the2-chloro-5-sulfamylbenzoic acid derivatives from DE 2145686.

Accordingly, the invention relates to compounds of the formula I

in which

X, R1, R2, R3 are, independently of one another, NR6R7, (CH₂)-pyridyl,(CH₂)_(n)-phenyl, where n can be 0-6 and the phenyl radical can besubstituted up to two times by F, Cl, Br, CF₃, NH₂, CN, OCF₃,O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COO(C₁-C₆)-alkyl, COO(C₃-C₆)-cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂;

(C₁-C₈)-alkyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,morpholinyl, tetrahydropyridinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, it being possible for each of the rings to besubstituted by phenyl, (C₁-C₆)-alkyl-phenyl, —OH, (C₁-C₈)-alkyl,(C₁-C₆)-alkyl-OH, O-phenyl, S-phenyl, (CO)—(C₁-C₆)-alkyl, (CO)-phenyl,where the phenyl substituent is unsubstituted or substituted up to twotimes by F, Cl, Br, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COOH, COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, CONH(C₃-C₆)cycloalkyl, NH₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl;

R6 and R7 are, independently of one another, H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl—OH, (C₁-C₆)-alkyl-NH2, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—C(O)—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl-di-phenyl,(C₁-C₆)-alkyl-O-phenyl, CHO, CO-phenyl,

 (CH₂)_(n)—Ar, where n can be 0-6, and Ar can be equal to phenyl,biphenylyl, 1- or 2-naphthyl, 1- or 2-tetrahydrofuranyl, 2-, 3- or4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4-or 5-oxazolyl, 1-pyrazolyl, 3-, 4- or 5-isoxazolyl, (C₃-C₆)-cycloalkyl,piperidinyl, pyrrolidinyl, oxopyridyl, 2- or 3-pyrrolyl, 2- or3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,2-(1,3,5-triazinyl), 2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl,2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl,indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4- or -5-yl and Ar canbe substituted up to two times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—CH₂—O, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, COOH,COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, CONH(C₃-C₆)cycloalkyl, NH₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, (CH₂)_(n)-phenyl,O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl, SO₂—(CH₂)_(n)-phenyl, wheren=0-3;

and their physiologically acceptable salts.

Preference is given to compounds of the formula I in which one or moreradical(s) is/are as defined below:

R1, R2 are, independently of one another, NR6R7, pyrrolidinyl,piperidinyl, piperazinyl, tetrahydropyridyl, it being possible for eachof the rings to be substituted by phenyl, (C₁-C₆)-alkyl-phenyl,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-OH, O-phenyl, S-phenyl, (CO)—(C₁-C₆)-alkyl,(CO)-phenyl, where the phenyl substituent is unsubstituted orsubstituted up to two times by F, Cl, Br, CF₃, CN, OCF₃,O—(C₁-C₆)-alkyl, S-(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COOH, COO(C₁-C₆)-alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, NH₂, NH—CO—(C₁-C₆)-alkyl, NH—CO-phenyl;

R6, R7 are, independently of one another, H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—C(O)—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂,

 (CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl,biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2-,4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3- or 5-isoxazolyl,(C₃-C₆)-cycloalkyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl,2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl orindol-3-yl, indol-5-yl and Ar can be substituted up to two times by F,Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COOH, COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,NH₂, NH—CO-phenyl, (CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl,S—(CH₂)_(n)-phenyl, where n=0-3;

X, R3 are, independently of one another, NR8R9, pyrrolidinyl,piperidinyl, morpholinyl, (C₁-C₈)-alkyl, (CH₂)_(n)-phenyl, where n=0-6and the phenyl radical can be substituted up to two times by F, Cl, Br,CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₆)cycloalkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂;

R8, R9 are, independently of one another, H, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl,SO₂-benzyl, SO₂-benzyl-OCH₃, (CH₂)_(n)—Ar, where n can be 0-6 and Ar canbe equal to phenyl or thienyl and Ar can be substituted up to two timesby F, Cl, Br, CF₃, NO₂, CN, OCF₃, O—CH₂—O, O—(C₁-C₆)-alkyl,S—(C₁-C₆)-alkyl, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, NH—CO-phenyl, (CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl,S—(CH₂)_(n)-phenyl, SO₂—(CH₂)_(n)-phenyl, where n=0-2;

and their physiologically acceptable salts.

Particular preference is given to compounds of the formula I in whichone or more radical(s) is/are as defined below:

R1, R2 are, independently of one another, NR6R7, piperidinyl,piperazinyl, tetrahydropyridyl, it being possible for each of the ringsto be substituted by phenyl, (C₁-C₆)-alkyl-phenyl, (C₁-C₆)-alkyl,(CO)—(C₁-C₆)-alkyl;

R6, R7 are, independently of one another, H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂,(CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl, 2-, 3-or 4-pyridyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-or 4-morpholinyl and Ar can be substituted up to two times by F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, COOH,NH₂,(CH₂)_(n)-phenyl, where n can be 0-3;

X is NR8R9, piperazinyl, (C₁-C₆)-alkyl, (CH₂)_(n)-phenyl, where n can be0-6;

R3 is NR10R11, piperazinyl;

R8, R9 are, independently of one another, H, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl,SO₂-benzyl, SO₂-benzyl-OCH₃, (CH₂)_(n)—Ar, where n can be 0-6 and Ar canbe equal to phenyl or thienyl;

R10, R11 are, independently of one another, H, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl,SO₂-benzyl, SO₂-benzyl-OCH₃, (CH₂)_(n)—Ar, where n can be 0-6 and Ar canbe equal to phenyl or thienyl;

and their physiologically acceptable salts.

Very particular preference is given to compounds of the formula I inwhich one or more radical(s) is/are as defined below:

R1, R2 are, independently of one another, NR6R7, piperidinyl,piperazinyl, tetrahydropyridyl, it being possible for each of the ringsto be substituted by phenyl, (C₁-C₆)-alkyl-phenyl, (C₁-C₆)-alkyl,(CO)—(C₁-C₆)-alkyl;

R6, R7 are, independently of one another, H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂,(CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl, 2-, 3-or 4-pyridyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-or 4-morpholinyl and Ar can be substituted up to two times by F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, COOH, NH₂,(CH₂)_(n)-phenyl, where n can be 0-3;

X is (C₁-C₆)-alkyl, (CH₂)_(n)-phenyl, where n can be 0-6;

R3 is NR10R11, piperazinyl;

R10, R11 are, independently of one another, H, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl,SO₂-benzyl, SO₂-benzyl-OCH₃, (CH₂)_(n)—Ar, where n can be 0-6 and Ar canbe equal to phenyl or thienyl;

and their physiologically acceptable salts.

The invention relates to compounds of the formula I in the form of theirracemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof. The alkyl, alkenyl and alkynylradicals in the substituents X, R1, R2, R3, R6, R7, R8, R10 and R11 maybe either straight-chain or branched.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because their solubility in water is higher than that ofthe initial or basic compounds. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of compounds of the formula I are salts of inorganicacids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric,nitric, sulfonic and sulfuric acids, and organic acids such as, forexample, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic,fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic,malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric andtrifluoroacetic acids. Suitable pharmaceutically acceptable basic saltsare ammonium salts, alkali metal salts (such as sodium and potassiumsalts) and alkaline earth metal salts (such as magnesium and calciumsalts).

Salts with a pharmaceutically unacceptable anion likewise fall withinthe scope of the invention as useful intermediates for preparing orpurifying pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.

Preference is given to the salts of methanesulfonic acid,toluenesulfonic acid, maleic acid and phosphoric acid.

Particular preference is given to the methanesulfonates of the compoundsof the formula I.

The invention furthermore relates to physiologically functionalderivatives of the compounds of the formula I. The term “physiologicallyfunctional derivative” used herein refers to any physiologicallytolerated derivative of a compound according to the invention, forexample an ester, which is able on administration to a mammal, such as,for example, a human, to form (directly or indirectly) such a compoundor an active metabolite thereof.

A further aspect of this invention is the use of prodrugs of thecompounds of the formula I. Such prodrugs can be metabolized in vivo toa compound of the formula I. These prodrugs may themselves be active ornot.

The compounds of the formula I may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the formula I lie within thescope of the invention and are a further aspect of the invention.

All references hereinafter to “compound(s) of formula (I)” refer tocompound(s) of the formula (I) as described above, and the salts,solvates and physiologically functional derivatives thereof as describedherein.

The amount of a compound of formula (I) which is necessary to achievethe desired biological effect depends on a number of factors, forexample the specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. In general,the daily dose is in the range from 0.3 mg to 100 mg (typically from 3mg to 50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can most suitably be administered as infusionof from 10 ng to 100 ng per kilogram and per minute. Suitable infusionsolutions for these purposes may contain, for example, from 0.1 ng to 10mg, typically from 1 ng to 10 mg, per milliliter. Single doses maycontain, for example, from 1 mg to 10 g of the active ingredient. It isthus possible for ampoules for injections to contain, for example, from1 mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, tablets or capsules, to contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the caseof pharmaceutically acceptable salts, the aforementioned weight data arebased on the weight of the salt of the compound of the formula (I). Forthe prophylaxis or therapy of the abovementioned conditions, thecompounds of formula (I) themselves can be used as the compound, butthey are preferably in the form of a pharmaceutical composition with anacceptable carrier. The carrier must, of course, be acceptable in thesense that it is compatible with the other ingredients of thecomposition and is not hazardous for the patient's health. The carriermay be a solid or a liquid or both and is preferably formulated with thecompound as a single dose, for example as a tablet which may containfrom 0.05% to 95% by weight of the active ingredient. Furtherpharmaceutically active substances may likewise be present, includingother compounds of formula (I). The pharmaceutical compositionsaccording to the invention can be produced by one of the knownpharmaceutical methods which essentially consist in mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions according to the invention are thosesuitable for oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration although the most suitable mode ofadministration in each individual case depends on the nature andseverity of the condition to be treated and on the nature of thecompound of formula (I) used in each case. Coated formulations andcoated slow-release formulations also lie within the scope of theinvention. Formulations resistant to acid and gastric fluid arepreferred. Suitable coatings resistant to gastric fluid comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, lozengesor tablets, each of which contain a defined amount of the compound offormula (I); as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional ingredients) are brought into contact. In general, thecompositions are produced by uniform and homogeneous mixing of theactive ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form, such as, for example, a powder or granules, whereappropriate mixed with a binder, lubricant, inert diluent and/or a(plurality of) surface-active/dispersing agent(s) in a suitable machine.Molded tablets can be produced by molding the compound which is inpowder form and is moistened with an inert liquid diluent in a suitablemachine.

Pharmaceutical compositions suitable for peroral (sublingual)administration comprise lozenges which contain a compound of formula (I)with a flavoring, normally sucrose and gum arabic or tragacanth, andpastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabric.

Suitable pharmaceutical compositions for parenteral administrationpreferably comprise sterile aqueous preparations of a compound offormula (I), which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions according to the invention generally contain from 0.1 to 5%by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application to the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%. Transdermal administration is also possible.Suitable pharmaceutical compositions for transdermal uses can be in theform of single plasters which are suitable for long-term close contactwith the patient's epidermis. Such plasters suitably contain the activeingredient in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.As a particular possibility, the active ingredient can be released asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986) byelectrotransport or iontophoresis.

The following preparations serve to illustrate the invention withoutrestricting it, however.

EXAMPLE A

Soft gelatin capsules containing 100 mg of active ingredient percapsule:

per capsule Active ingredient 100 mg Triglyceride mixture fractionated400 mg from coconut fat Capsule contents 500 mg

EXAMPLE B

Emulsion containing 60 mg of active ingredient per 5 ml:

per 100 ml emulsion Active ingredient 1.2 g Neutral oil q.s. Sodiumcarboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s. Glycerol,pure 0.2 to 2.0 g Flavoring q.s. Water (deionized or distilled) ad 100ml

EXAMPLE C

Rectal pharmaceutical form containing 40 mg of active ingredient persuppository:

per suppository Active ingredient 40 mg Suppository base ad 2 g

EXAMPLE D

Tablets containing 40 mg of active ingredient per tablet:

per tablet Active ingredient 40 mg Lactose 600 mg Corn starch 300 mgSoluble starch 20 mg Magnesium stearate 40 mg 1000 mg

EXAMPLE E

Coated tablets containing 50 mg of active ingredient per coated tablet:

per coated tablet Active ingredient 50 mg Corn starch 100 mg Lactose 60mg Sec. calcium phosphate 30 mg Soluble starch 5 mg Magnesium stearate10 mg Colloidal silica 5 mg 260 mg

EXAMPLE F

The following formulas are suitable for producing the contents of hardgelatin capsules:

a) Active ingredient 100 mg Corn starch 300 mg 400 mg b) Activeingredient 140 mg Lactose 180 mg Corn starch 180 mg 500 mg

EXAMPLE G

Drops can be produced in accordance with the following formula (100 mgof active ingredient in 1 ml = 20 drops):

Active ingredient 10 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 gEthanol 96% pure 5 ml Demineralized water ad 100 ml

The invention also relates to a process for preparing the compounds ofthe formula I, which comprises preparing compounds of the formula I asshown in the following reaction diagram:

The examples detailed below serve to illustrate the invention withoutrestricting it, however. The stated decomposition points are notcorrected and generally depend on the heating rate.

TABLE 1 Examples Formula I

Mo- lecu- lar MS Ex. R1 R2 R3 X Empirical formula mass (M + H⁺) 1NH-ethyl-pyrrolidinyl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenylC32 H42 N6 O3 S 590.8 591.3 2 NH-propyl-phenyl piperazin-1-yl-4-CH₃N(CH₃)-phenyl N(CH₃)-phenyl C35 H41 N5 O3 S 611.8 612.4 3NH-ethyl-phenyl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenyl C34 H39N5 O3 S 597.8 598.4 4 NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃N(CH₃)-phenyl N(CH₃)-phenyl C38 H46 N6 O3 S 666.9 667.4 5NH—CH₂-pyrid-2-yl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenyl C32H36 N6 O3 S 584.7 585.3 6 NH-ethyl-morpholin-4-yl piperazin-1-yl-4-CH₃N(CH₃)-phenyl N(CH₃)-phenyl C32 H42 N6 O4 S 606.8 607.4 7piperazin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenylC36 H42 N6 O3 S 638.8 639.3 8 NH-4-t-butyl-benzyl piperazin-1-yl-4-CH₃N(CH₃)-phenyl N(CH₃)-phenyl C37 H45 N5 O3 S 639.9 640.3 9piperidin-1-yl-4-benzyl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenylC38 H45 N5 O3 S 651.9 652.3 10 piperidin-1-yl-4-phenylpiperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenyl C37 H43 N5 O3 S 637.8638.3 11 piperazin-1-yl-4-acetyl piperazin-1-yl-4-CH₃ N(CH₃)-phenylN(CH₃)-phenyl C32 H40 N6 O4 S 604.8 605.4 12 N(ethyl)-ethyl-N(CH₃)₂piperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenyl C32 H44 N6 O3 S 592.8593.4 13 NH-ethyl-phenyl piperazin-1-yl-4-CH₃ N(CH₃)-phenyl CH₃ C28 H34N4 O3 S 506.7 507.2 14 NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃N(CH₃)-phenyl CH₃ C32 H41 N5 O3 S 575.8 576.3 15 NH-ethyl-phenylpiperazin-1-yl-4-CH₃ N(ethyl)₂ CH₂-phenyl C31 H40 N4 O3 S 548.7 549.3 16NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃ N(ethyl)₂ CH₂-phenyl C35H47 N5 O3 S 617.9 618.4 17 NH-ethyl-N-pyrrolidinylNH-piperidin-4-yl-1-benzyl N(CH₃)-phenyl N(CH₃)-phenyl C39 H47 N5 O3 S665.9 666.3 18 NH-ethyl-N-pyrrolidinyl NH—CH₂-pyrid-2-yl N(CH₃)-phenylN(CH₃)-phenyl C33 H38 N6 O3 S 598.8 599.3 19 NH-ethyl-N-pyrrolidinylNH-ethyl-phenyl N(CH₃)-phenyl N(CH₃)-phenyl C35 H41 N5 O3 S 611.8 612.320 NH-ethyl-N-pyrrolidinyl piperidin-1-yl-4-phenyl N(CH₃)-phenylN(CH₃)-phenyl C38 H45 N5 O3 S 651.9 652.3 21 NH-ethyl-N-pyrrolidinylpiperazin-1-yl-4-phenyl N(CH₃)-phenyl N(CH₃)-phenyl C37 H44 N6 O3 S652.9 653.3 22 piperidin-1-yl-4-benzyl NH-ethyl-N-pyrrolidinylN(CH₃)-phenyl N(CH₃)-phenyl C39 H47 N5 O3 S 665.9 666.3 23NH—CH₂-pyrid-2-yl NH-ethyl-N-pyrrolidinyl N(CH₃)-phenyl N(CH₃)-phenylC33 H38 N6 O3 S 598.8 599.3 24 NH-ethyl-phenyl NH-ethyl-N-pyrrolidinylN(CH₃)-phenyl N(CH₃)-phenyl C35 H41 N5 O3 S 611.8 612.3 25piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl N(CH₃)-phenylN(CH₃)-phenyl C38 H45 N5 O3 S 651.9 652.3 26 piperazin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl N(CH₃)-phenyl N(CH₃)-phenyl C37 H44 N6 O3 S652.9 653.4 27 NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃piperidin-1-yl CH₃ C30 H43 N5 O3 S 553.8 554.3 28piperazin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ piperidin-1-yl CH₃ C28 H39N5 O3 S 525.7 526.3 29 NH-butyl-phenyl piperazin-1-yl-4-CH₃piperidin-1-yl CH₃ C28 H40 N4 O3 S 512.7 513.3 30piperidin-1-yl-4-benzyl piperazin-1-yl-4-CH₃ piperidin-1-yl CH₃ C30 H42N4 O3 S 538.8 539.3 31 NH—CH₂-pyrid-2-yl piperazin-1-yl-4-CH₃ N(ethyl)₂CH₂-phenyl C29 H37 N5 O3 S 535.7 536.3 32 piperazin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ CH₂-phenyl C34 H47 N5 O3 S 605.8 606.333 piperazin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ NH-propyl-OCH₃ CH₃ C27H39 N5 O4 S 529.7 530.3 34 piperidin-1-yl-4-phenyl piperazin-1-yl-4-CH₃NH-propyl-OCH₃ CH₃ C28 H40 N4 O4 S 528.7 529.3 35piperidin-1-yl-4-benzyl piperazin-1-yl-4-CH₃ NH-propyl-OCH₃ CH₃ C29 H42N4 O4 S 542.7 543.3 36 NH-piperidin-4-yl piperazin-4-yl-2-onN(CH₃)-phenyl N(CH₃)-phenyl C30 H36 N6 O4 S 576.7 577.4 37piperidin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ piperidin-1-ylpiperidin-1-yl C33 H47 N5 O3 S 593.8 594.3 38 NH-ethyl-phenylpiperazin-1-yl-4-CH₃ piperidin-1-yl piperidin-1-yl C30 H43 N5 O3 S 553.8554.3 39 NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃ piperidin-1-ylpiperidin-1-yl C34 H49 N5 O3 S 607.9 608.4 40 piperidin-1-yl-4-phenylpiperazin-1-yl-4-CH₃ NH—CH₂-thien- NH—CH₂-thien- C33 H39 N5 O3 S3 649.9650.2 2-yl 2-yl 41 NH-butyl-phenyl piperazin-1-yl-4-CH₃ NH—CH₂-thien-NH—CH₂-thien- C32 H39 N5 O3 S3 637.9 638.2 2-yl 2-yl 42piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl C35 H48N4 O3 S 604.9 605.3 43 NH-propyl-phenyl piperazin-1-yl-4-CH₃N(CH₃)-phenyl N(CH₃)-phenyl C35 H41 N5 O3 S 611.8 612.3 44 NH-benzylpiperazin-1-yl-4-CH₃ N(CH₃)-phenyl N(CH₃)-phenyl C33 H37 N5 O3 S 583.8584.2 45 NH-(p-CF₃O-benzyl) piperazin-1-yl-4-CH₃ N(CH₃)-phenylN(CH₃)-phenyl C34 H36 F3 N5 O4 S 667.7 668.2 461,2,5,6-tetrahydropyrid-1- piperazin-1-yl-4-CH₃ NH-propyl-OCH₃ CH₃ C28H38 N4 O4 S 526.7 527.3 yl-4-phenyl 47 1,2,5,6-tetrahydropyrid-1-piperazin-1-yl-4-CH₃ piperidin-1-yl CH₃ C29 H38 N4 O3 S 522.7 523.3yl-4-phenyl 48 1,2,5,6-tetrahydropyrid-1- piperazin-1-yl-4-CH₃NH—CH₂-thien- NH—CH₂-thien- C33 H37 N5 O3 S3 647.9 648.1 yl-4-phenyl2-yl 2-yl 49 piperidin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ NH—C₂H₄-thien-NH—C₂H₄-thien- C35 H43 N5 O3 S3 678.0 678.3 2-yl 2-yl 50 NH-phenethylpiperazin-1-yl-4-CH₃ NH—C₂H₄-thien- NH—C₂H₄-thien- C32 H39 N5 O3 S3637.9 638.2 2-yl 2-yl 51 NH-piperidin-4-yl-1-benzyl piperazin-1-yl-4-CH₃NH—C₂H₄-thien- NH—C₂H₄-thien- C36 H46 N6 O3 S3 707.0 707.2 2-yl 2-yl 52piperazin-1-yl-4-phenyl piperazin-1-yl-4-CH₃ NH—C₂H₄-thien-NH—C₂H₄-thien- C34 H42 N6 O3 S3 678.9 679.2 2-yl 2-yl 53piperidin-1-yl-4-benzyl NH-ethyl-N-pyrrolidinyl NH-pentyl CH₃ C31 H46 N4O3 S 554.8 555.4 54 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinylNH-pentyl CH₃ C30 H44 N4 O3 S 540.8 541.4 55 1,2,5,6-tetrahydropyrid-1-NH-ethyl-N-pyrrolidinyl NH-pentyl CH₃ C30 H42 N4 O3 S 538.8 539.3yl-4-phenyl 56 piperidin-1-yl-4-benzyl piperazin-1-yl-4-CH₃Piperidin-1-yl CH₃ C30 H42 N4 O3 S 538.8 539.3 57piperidin-1-yl-4-benzyl NH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ CH₃ C30H44 N4 O4 S 556.8 557.4 58 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ CH₃ C29 H42 N4 O4 S 542.7 543.459 1,2,5,6-tetrahydropyrid-1- NH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ CH₃C29 H40 N4 O4 S 540.7 541.4 yl-4-phenyl 60 NH-piperidin-4-yl-1-benzylNH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ CH₃ C30 H45 N5 O4 S 571.8 572.461 piperidin-1-yl-4-phenyl —N(acetyl)-ethyl-N- NH-propyl-OCH₃ CH₃ C31H44 N4 O5 S 584.8 585.3 pyrrolidinyl 62 piperidin-1-yl-4-benzylN(methyl)-ethyl-N(CH₃)₂ NH-propyl-OCH₃ CH₃ C29 H44 N4 O4 S 544.8 545.363 piperidin-1-yl-4-phenyl N(methyl)-ethyl-N(CH₃)₂ NH-propyl-OCH₃ CH₃C28 H42 N4 O4 S 530.7 531.4 64 1,2,5,6-tetrahydropyrid-1-N(methyl)-ethyl-N(CH₃)₂ NH-propyl-OCH₃ CH₃ C28 H40 N4 O4 S 528.7 529.3yl-4-phenyl 65 NH-piperidin-4-yl-1-benzyl N(methyl)-ethyl-N(CH₃)₂NH-propyl-OCH₃ CH₃ C29 H45 N5 O4 S 559.8 560.4 66piperidin-1-yl-4-phenyl N(methyl)-ethyl-N(CH₃)₂ piperidin-1-yl CH₃ C29H42 N4 O3 S 526.7 527.4 67 piperidin-1-yl-4-benzylN(methyl)-ethyl-N(CH₃)₂ piperidin-1-yl CH₃ C30 H44 N4 O3 S 540.8 541.468 piperidin-1-yl-4-benzyl NH-ethyl-N-pyrrolidinyl piperidin-1-yl CH₃C31 H44 N4 O3 S 552.8 553.4 69 NH-piperidin-4-yl-1-benzylNH-ethyl-N-pyrrolidinyl piperidin-1-yl CH₃ C31 H45 N5 O3 S 567.8 568.470 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl N(ethyl)₂ benzyl C35H46 N4 O3 S 602.8 603.4 71 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl-3-OCH₃ C36 H50 N4 O4 S 634.9635.4 72 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzylC36 H50 N4 O3 S 618.9 619.4 73 piperidin-1-yl-4-(p-F-NH-ethyl-N-pyrrolidinyl NH-pentyl benzyl C36 H47 F N4 O3 S 634.9 635.2phenyl) 74 piperidin-1-yl-4-(p-OCH₃- NH-ethyl-N-pyrrolidinyl NH-pentylbenzyl C37 H50 N4 O4 S 646.9 647.2 phenyl) 75 piperidin-1-yl-4-(p-CH₃-NH-ethyl-N-pyrrolidinyl NH-pentyl benzyl C37 H50 N4 O3 S 630.9 631.2phenyl) 76 piperidin-1-yl-4-(p-F- N(ethyl)-ethyl-N(CH₃)₂ NH-pentylbenzyl C36 H49 F N4 O3 S 636.9 637.2 phenyl) 77piperidin-1-yl-4-(p-OCH₃- N(ethyl)-ethyl-N(CH₃)₂ NH-pentyl benzyl C37H52 N4 O4 S 648.9 649.3 phenyl) 78 piperidin-1-yl-4-(p-CH₃-N(ethyl)-ethyl-N(CH₃)₂ NH-pentyl benzyl C37 H52 N4 O3 S 632.9 633.3phenyl) 79 piperidin-1-yl-4-hydroxy NH-ethyl-N-pyrrolidinyl NH-pentylbenzyl C30 H44 N4 O4 S 556.8 557.4 80 piperidin-1-yl-4-phenoxyN(ethyl)-ethyl-N(CH₃)₂ NH-pentyl benzyl C35 H48 N4 O4 S 620.8 621.4 81piperidin-1-yl-4-phenoxy NH-ethyl-N-pyrrolidinyl NH-pentyl benzyl C36H48 N4 O4 S 632.9 633.4 82 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ 2,4-F₂-benzyl C35 H46 F2 N4 O3 S 640.8641.4 83 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl N(ethyl)₂4-CH₃-benzyl C36 H48 N4 O3 S 616.9 617.4 84 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl N(ethyl)₂ 3-OCH₃-benzyl C36 H48 N4 O4 S 632.9633.4 85 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N-pyrrolidinyl N(ethyl)₂3-OCH₃-benzyl C38 H52 N4 O4 S 660.9 661.5 86 piperidin-1-yl-4-benzylN(ethyl)-ethyl-N-pyrrolidinyl N(ethyl)₂ 3-OCH₃-benzyl C39 H54 N4 O4 S675.0 675.5 87 piperidin-1-yl-4-phenyl NH-propyl-N-(2-oxo- N(ethyl)₂benzyl C36 H46 N4 O4 S 630.9 631.4 pyrrolidinyl 88piperidin-1-yl-4-phenyl NH-(1-methyl-butyl)- N(ethyl)₂ benzyl C38 H54 N4O3 S 646.9 647.5 N(ethyl)₂ 89 piperidin-1-yl-4-phenylNH-propyl-pyrrolidinyl N(ethyl)₂ benzyl C36 H48 N4 O3 S 616.8 617.4 90piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl NH(ethyl) benzyl C33 H42N4 O3 S 574.8 575.3 91 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinylN(ethyl)₂ 3-(OCF₃)-benzyl C36 H45 F3 N4 O4 S 686.8 687.2 92piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl N(ethyl)₂2,4-di-F-benzyl C35 H44 F2 N4 O3 S 638.8 639.4 93piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl NH₂ benzyl C31 H38 N4 O3S 546.7 547.3 94 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinylNH-butyl benzyl C35 H46 N4 O3 S 602.8 603.3 95 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl NH-hexyl benzyl C37 H50 N4 O3 S 630.9 631.3 96piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ 3,5-(OMe₂)- C37H54 N4 O5 S 666.2 667.[lacuna] benzyl 97 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ butyl C32 H50 N4 O3 S 570.8 571.3 98piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N-pyrrolidinyl NH-butyl benzylC37 H50 N4 O3 S 630.9 631.3 99 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N-pyrrolidinyl NH-hexyl benzyl C39 H54 N4 O3 S 658.9659.4 100 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N-pyrrolidinyl NH-ethylbenzyl C35 H46 N4 O3 S 602.8 603.2 101 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N-pyrrolidinyl piperidin-1-yl-4- benzyl C44 H56 N4 O3 S718 719.3 phenyl 102 NH-propyl-phenyl NH-ethyl-N-pyrrolidinyl NH-pentylmethyl C28 H42 N4 O3 S 514.7 515.3 103 NH-butyl-phenylNH-ethyl-N-pyrrolidinyl NH-pentyl methyl C29 H44 N4 O3 S 528.8 529.3 104NH-1-ethyl-2,2(phenyl)₂ NH-ethyl-N-pyrrolidinyl NH-pentyl methyl C33 H44N4 O3 S 576.8 577.3 105 NH-(p-t-butyl-benzyl) NH-ethyl-N-pyrrolidinylNH-pentyl methyl C30 H46 N4 O3 S 542.8 543.4 106 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl NH-ethyl methyl C27 H38 N4 O3 S 498.7 499.3 107piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ NH-pentyl-5- benzyl C36H50 N4 O4 S 634.9 635.3 hydroxy 108 piperidin-1-yl-4-phenylN(CH₃)-ethyl-NHCH₃ NH-pentyl benzyl C34 H46 N4 O3 S 590.8 591.3 109piperidin-1-yl-4-phenyl N(CH₃)-ethyl-N(CH₃)₂ NH-pentyl benzyl C35 H48 N4O3 S 604.9 605.3 110 piperidin-1-yl-4-phenyl N(CH₃)-ethyl-NHCH₃NH-pentyl-5-OH benzyl C34 H46 N4 O4 S 606.8 607.3 111piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl-3-OCF₃C36 H47 F3 N4 O4 S 688.9 689.2 112 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ —CH₂-pyrid-3-yl C34 H47 N5 O3 S 605.8606.3 113 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂benzyl-4-CF₃ C36 H47 F3 N4 O3 S 672.9 673.3 114 NH-butyl-phenylNH-ethyl-N-pyrrolidinyl NH-ethyl methyl C26 H38 N4 O3 S 486.7 487.3 115piperidin-1-yl-4-benzyl NH-ethyl-N-pyrrolidinyl NH-ethyl methyl C28 H40N4 O3 S 512.7 513.3 116 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N(CH₃)₂N(ethyl)₂ benzyl-4-cyano C36 H47 N5 O3 S 629.9 630.3 117NH-1-ethyl-2,2(phenyl)₂ N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl-4-CF₃C39 H47 F3 N4 O3 S 708.9 709.0 118 NH-butyl-phenylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl-4-cyano C35 H47 N5 O3 S 617.9618.3 119 NH-butyl-phenyl N(methyl)-ethyl-N- NH-pentyl methyl C30 H46 N4O3 S 542.8 543.3 pyrrolidinyl 120 piperidin-1-yl-4-phenylN(methyl)-ethyl-NH-ethyl NH-pentyl benzyl C35 H48 N4 O3 S 604.9 605.3121 1,2,3,4-tetrahydro- N(methyl)-ethyl-N- NH-pentyl methyl C29 H42 N4O3 S 526.7 527.3 isoquinolin-2-yl pyrrolidinyl 122 1,2,3,4-tetrahydro-NH-ethyl-N-pyrrolidinyl N(ethyl)₂ benzyl-3-OCH₃ C34 H44 N4 O4 S 604.8605.3 isoquinolin-2-yl 123 piperidin-1-yl-4-benzylN(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂ benzyl-4-CH₃ C37 H52 N4 O3 S 632.9633.4 124 1,2,3,4-tetrahydro- N(ethyl)-ethyl-N(CH₃)₂ N(ethyl)₂benzyl-4-CH₃ C34 H46 N4 O3 S 590.8 591.5 isoquinolin-2-yl 1251,2,3,4-tetrahydro- NH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ methyl C27H38 N4 O4 S 514.7 515.3 isoquinolin-2-yl 126 1,2,3,4-tetrahydro-N(ethyl)-ethyl-N-pyrrolidinyl N(ethyl)₂ benzyl-3-OCH₃ C36 H48 N4 O4 S632.9 633.6 isoquinolin-2-yl 127 NH-1-ethyl-2,2(phenyl)₂NH-ethyl-N-pyrrolidinyl NH-propyl-OCH₃ methyl C32 H42 N4 O4 S 578.8579.3 128 piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl NH-butylbenzyl-4-CH₃ C36 H48 N4 O3 S 616.9 617.6 129 piperidin-1-yl-4-phenylN(butyl)-ethyl-N-pyrrolidinyl NH-pentyl methyl C34 H52 N4 O3 S 596.9597.3 130 piperidin-1-yl-4-phenyl N(butyl)-ethyl-N-pyrrolidinylN(ethyl)₂ methyl C33 H50 N4 O3 S 582.9 583.2 131 piperidin-1-yl-4-phenylNH-propyl-N-pyrrolidinyl N(butyl)₂ methyl C34 H52 N4 O3 S 596.9 597.2132 piperidin-1-yl-4-phenyl N(ethyl)-ethyl-N-pyrrolidinyl N(butyl)₂methyl C35 H54 N4 O3 S 610.9 611.2 133 piperidin-1-yl-4-phenylNH-ethyl-N-piperidinyl NH(pentyl) methyl C31 H46 N4 O3 S 554.8 555.3 134piperidin-1-yl-4-phenyl-4- NH-ethyl-N-pyrrolidinyl NH-pentyl methyl C30H45 N5 O3 S 555.8 556.3 NH₂ 135 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl NH-butyl benzyl- C37 H50 N4 O5 S 662.9 663.63,5(OCH₃)₂ 136 piperidin-1-yl-4-(4-NH₂- N(butyl)-ethyl-N-pyrrolidinylN(ethyl)₂ methyl C33 H51 N5 O3 S 597.9 598.5 phenyl) 137piperidin-1-yl-4-(4-NH₂- N(ethyl)-ethyl-N-pyrrolidinyl NH-butyl methylC31 H47 N5 O3 S 569.8 570.4 phenyl) 138 piperidin-1-yl-4-phenylNH-ethyl-N-pyrrolidinyl NH-hexyl methyl C31 H46 N4 O3 S 554.8 555.4 139piperidin-1-yl-4-phenyl NH-ethyl-N-pyrrolidinyl NH-pentyl benzyl-3-NH₂C36 H49 N5 O3 S 631.9 632.4 140 piperidin-1-yl-4-phenylN(ethyl)-ethyl-N(CH₃)₂ NH-pentyl-NH₂ benzyl C36 H51 N5 O3 S 633.9 634.4

Example 141

Methanesulfonate of Example 54

20.0 g of the free base from Example 54 are dissolved in hot isopropanoland admixed with 5.1 ml of methanesulfonic acid. After cooling of thesolution to room temperature, the resulting suspension is stirred at atemperature between 0° C. and 5° C. for a further hour, and the productis then obtained by filtration. The crude product is recrystallized from200 ml of isopropanol and dried at 50° C. under reduced pressure. Thisgives 21.0 g of the salt of melting point 205° C.-208° C.

Example 142

Toluenesulfonate of Example 54

Example 143

Maleate of Example 54

The compounds of the formula I are distinguished by beneficial effectson lipid metabolism, and they are suitable in particular ashypolipidemics. The compounds can be employed alone or in combinationwith other lipid-lowering agents. Such other lipid-lowering agents arementioned, for example, in the Rote Liste, Chapter 58. The compounds aresuitable for the prophylaxis and, in particular, for the treatment ofhyperlipidemia.

Arteriosclerosis is a complex disorder of the metabolic and circulatorysystems. Elevated plasma LDL cholesterol is one of the main riskparameters for this disorder. In humans, LDL cholesterol is mostlyremoved from the blood circulation via the LDL receptor in the liver. Areduction in the plasma LDL cholesterol reduces the risk ofarteriosclerosis and thus also the overall mortality. The compoundsaccording to the invention are thus also suitable for the prophylaxisand for the treatment of arteriosclerotic disorders.

The activity of the compounds was tested as follows:

1) In vitro Determination of LDL Receptor Induction Using the LuciferaseAssay

LDL-receptor induction is determined using the Luciferase assay asfollows: for this purpose, a regulatory DNA fragment (4 kb) of the humanLDL receptor gene which contains the complete promoter region is coupledto the firefly Luciferase reporter gene and stably transfixed into aHep-G2 cell line. Cells from this line were seeded out oncollagen-coated 96-well plates in MEM (minimum essential medium). After24 hours in culture, the test substances, dissolved in DMSO, were addedin final concentrations of 10 nM to 10 μM (final DMSO concentration=2%).The substances were incubated for 12-18 hours overnight (4 wells/conc.in each case), then D-luciferin was added as substrate for theLuciferase, and the luminescence was measured. The measured luminescenceas a percentage of the control (control=100%) incubated only with DMSOindicates the extent of the relative LDL-receptor induction (Table 2).

Further details of the method are described in: Current Protocols inMolecular Biology, F. M. Ausubel, R. Brent, R. E. Kingston, D. D. Moore,J. G. Seidman, J. A. Smith and Kevin Struhl editors, J. Wiley and SonsInc., U.S.A.

TABLE 2 LDL-receptor induction by selected examples in % of the controlLDL-receptor induction (% of control); concentration of Example the testcompound in μM in ( ) 2 225% (1.5 μM) 3 276% (1.5 μM) 4 190% (0.15 μM) 9170% (0.15 μM) 14 176% (1.5 μM) 22 224% (0.15 μM) 25 346% (1.5 μM); 152%(0.05 μM) 30 255% (1.5 μM); 199% (0.15 μM) 34 291% (4 μM); 210% (0.15μM) 37 227% (1.5 μM); 204% (0.15 μM) 39 185% (0.15 μM) 42 149% (0.05 μM)53 221% (0.15 μM); 197% (0.05 μM) 54 223% (0.15 μM) 57 222% (0.15 μM) 62205% (0.05 μM) 67 203% (0.15 μM) 76 244% (0.15 μM) 78 200% (0.15 μM) 80239% (0.15 μM) 82 227% (0.15 μM) 83 212% (0.15 μM) 84 240% (0.05 μM) 91231% (0.05 μM) 96 196% (0.05 μM) 105 236% (0.05 μM) 107 288% (0.05 μM)113 217% (0.05 μM) 116 235% (0.05 μM) 141 280% (0.15 μM) 142 281% (0.15μM) 143 308% (0.15 μM)

2) In vivo Determination of Reduction in LDL Cholesterol in Hamsters

Cholesterol-lowering effect of LDL-receptor inducers in hyperlipemichamsters

In this animal experiment, the effect of LDL-receptor inducers afterbolus administration to hamsters on a lipid-rich diet was investigated.

The test animals used were male Syrian hamsters (Charles River) with anaverage body weight of 100-120 g at the start of adaptation. The animalswere divided into groups (n=6) on the basis of body weight. Severehyperlipidemia was induced by feeding with a diet supplemented with 15%butter and 3% cholesterol. The treatment started after preliminaryfeeding for 2 weeks. The test substances were administered orally bygavage once a day over a period of 10 days. The plasma lipid level wasanalyzed after 10 days.

Table 3 shows the relative changes in the lipid level in % compared withplacebo-treated control animals.

TABLE 3 Relative change in the plasma lipid level in hyperlipidemichamsters after oral treatment for 10 days [%]. Treatment Total LDL Group(Ex. No./Dose) cholesterol cholesterol Triglycerides 1 Control I — — — 237 −21 −31 −46 20 mg/kg p.o. 3 53  −7 −52 +21 10 mg/kg p.o. 4 53 −16 −57−11 20 mg/kg p.o. 5 53 −17 −58 −23 40 mg/kg p.o.

The good lipid-lowering effect of the compounds according to theinvention is evident from the marked reduction in total cholesterol, LDLcholesterol and triglycerides.

A comparative test was carried out by the Luciferase assay describedabove using 2,4-dichloro-5-(3,5-dimethylpiperidinosulfamoyl)benzoic acidand the compound from Example 42.

2,4-Dichloro-5-(3,5-dimethylpiperidinosulfamoyl)benzoic acid

Luciferase Assay

LDL-receptor induction in %, compared with control Substance 4 μM 1.5 μM0.15 μM 0.05 μM Example 42 278 250 219 204 2,4-Dichloro-5-(3,5-dimethyl-100 90 90 94 piperidinosulfamoyl)benzoic acid

Thus, the compounds of the formula I according to the invention exhibitconsiderably improved activity compared with2,4-dichloro-5-(3,5-dimethylpiperidinosulfamoyl)benzoic acid.

For detailed illustration of the preparation, one example (No. 42) isdescribed precisely below.

Example2-[(2-Dimethylaminoethyl)ethylamino]-N,N-diethyl-5-phenylmethane-sulfonyl-4-(4-phenylpiperidin-1-yl)benzamide(Table 1, Example 42) 1. Preparation of3-chlorosulfonyl-4-chloro-6-fluorobenzoic acid

At 20° C., 20 g (0.115 mol) of 4-chloro-2-fluorobenzoic acid are added alittle at a time with stirring to 100 ml of chlorosulfonic acid. Thereaction mixture is heated with stirring at 120° C. for 5 hours. Forwork-up, the cold reaction mixture is introduced dropwise with vigorousstirring into 5 l of an ice/water mixture. The resulting precipitate isfiltered off with suction, washed with water and then dried in a vacuumdrying cabinet at 50° C. for 1 hour.

This gives 61.5 g of 3-chlorosulfonyl-4-chloro-6-fluorobenzoic acid,colorless crystals of melting point 135° C.

2. Preparation of 5-carboxy-2-chloro-4-fluorobenzosulfinic acid disodiumsalt

71 g (0.563 mol; 2.5 equivalents) of sodium sulfite are dissolved in 200ml of water and, with ice-cooling, admixed with 61.5 g of the compoundfrom procedure 1. (3-chlorosulfonyl-4-chloro-6-fluorobenzoic acid). Byadding conc. aqueous sodium hydroxide solution, the pH of the solutionis adjusted to pH 9, and the solution is stirred at 20° C. for 6 hours.Using conc. aqueous hydrochloric acid, the solution is then acidified topH 1, resulting in the precipitation of the sulfinic acid formed. Thesulfinic acid is filtered off, the reaction product is dissolved in 600ml of water and the pH of the solution is adjusted to pH 10 by additionof conc. aqueous NaOH. The mixture is filtered through activated carbon,the solvent is removed under reduced pressure and the oily residue isthen crystallized by addition of 100 ml of acetone.

This gives 59.2 g of colorless crystals (93% of theory) which aredirectly reacted further.

3. Preparation of benzyl4-chloro-2-fluoro-5-phenylmethanesulfonyl-benzoate

28.3 g (0.1 mol) of the compound prepared under 2. are suspended in 250ml of N-methyl-2-pyrrolidone and admixed successively with 41 g (0.24mol) of benzyl bromide and 4.6 g (0.3 mol) of potassium carbonate. Thereaction mixture is stirred at 60° C. for 8 hours. For work-up, thereaction mixture is, after cooling to room temperature, added to 1.5liter of ice water, resulting, after 20 minutes, in the precipitation ofthe reaction product in the form of a colorless solid which is filteredoff.

This gives 38.9 g (93% of theory) of benzyl4-chloro-2-fluoro-5-phenylmethanesulfonylbenzoate; the compound isdirectly reacted according to 4., without further purification steps.

4. Preparation of 4-chloro-2-fluoro-5-phenylmethanesulfonylbenzoic acid

1.26 g (1.2 equivalents) of NaOH pellets are dissolved in 40 ml of waterand admixed with 11 g (26.3 mmol) of benzyl4-chloro-2-fluoro-5-phenylmethanesulfonylbenzoate, dissolved in 40 ml oftetrahydrofuran. The reaction solution is stirred at 20° C. for 3 hours.

For work-up the solution is then poured into 1 l of an ice/water mixtureand the pH is adjusted to 1.2 by adding conc. aqueous hydrochloric acid.After some time, the reaction product precipitates in the form ofcolorless crystals. 8.4 g (97.7% of theory) of melting point 180-184° C.are obtained.

5. Preparation of4-chloro-N,N-diethyl-2-fluoro-5-phenylmethanesulfonyl-benzamide

6.6 g (20 mmol) of the carboxylic acid from Example 4. are suspended in50 ml of thionyl chloride and the mixture is, with stirring, heated atreflux for 1 hour. The mixture is then concentrated under reducedpressure using a rotary evaporator, and the oily residue is dissolved in100 ml of absolute dichloromethane and, at −10° C., admixed dropwisewith 3.1 g (2.1 equivalents) of diethylamine. After the addition hasended, stirring at 20° C. is continued for 1 hour. The reaction mixtureis then repeatedly washed successively with saturated aqueousbicarbonate solution and water and dried using sodium sulfate, and thesolvent is removed under reduced pressure using a rotary evaporator. Theresulting crude product is purified by silica gel chromatography(particle size 40-63μ, from Merck Darmstadt) using n-heptane/ethylacetate 1:1 as mobile phase (R_(F)=0.52).

Removal of the mobile phase under reduced pressure using a rotaryevaporator gives 7.7 g of4-chloro-N,N-diethyl-2-fluoro-5-phenyl-methanesulfonylbenzamide (yieldquantitative).

6. Preparation of4-chloro-2-[(2-dimethylaminoethyl)ethylamino]-N,N-diethyl-5-phenylmethanesulfonylbenzamide

5.7 g (15 mmol) of4-chloro-N,N-diethyl-2-fluoro-5-phenylmethanesulfonyl-benzamide aredissolved in 50 ml of ethanol and, after addition of 2.6 g (22.5 mmol;1.5 equivalents) of N,N-dimethylethylenediamine, heated at reflux for 18hours. The solvent is then removed under reduced pressure and theresidue is taken up in 100 ml of dichloromethane and washed withsaturated aqueous bicarbonate solution, followed by repeated extractionwith in each case 30 ml of water. The organic phase is then dried oversodium sulfate and the solvent is removed under reduced pressure using arotary evaporator.

This gives 7.3 g of a pale yellow oil which is directly converted intothe final product of the reaction sequence (see procedure 7.).

7. Preparaiton of2-[(2-dimethylaminoethyl)ethylamino]-N,N-diethyl-5-phenylmethanesulfonyl-4-(4-phenylpiperidin-1-yl)benzamide(Ex. 42)

3.5 g (7.3 mmol) of4-chloro-2-[(2-dimethylaminoethyl)ethylamino]-N,N-diethyl-5-phenylmethanesulfonylbenzamidefrom procedure 6. are mixed with 5.9 g of 4-phenylpiperidine (5equivalents), prepared by hydrogenation of commercial4-phenyl-1,2,3,6-tetrahydropyridine, and the mixture is stirred at 150°C. for 5 hours. The mixture is then dissolved in 150 ml ofdichloromethane and extracted with saturated aqueous sodium bicarbonatesolution and water. The organic phase is dried over sodium sulfate andthe solvent is then removed under reduced pressure using a rotaryevaporator. The crude product is purified by chromatography on silicagel (particle size 40-63μ from Merck Darmstadt) as stationary phase,using ethyl acetate/methanol, mixing ratio 2:1.

This gives 4.5 g of2-[(2-dimethylaminoethyl)ethylamino]-N,N-diethyl-5-phenylmethanesulfonyl-4-(4-phenylpiperidin-1-yl)benzamide,pale yellow oil.

MS: C35 H48 N4 O3 S (604.9); mass spectrum 605.3 (M+H⁺).

We claim:
 1. A compound of the formula I

in which X, R1, R2, R3 are, independently of one another, NR6R7,CH₂-pyridyl, or (CH₂)_(n)-phenyl, where n can be 0-6 and the phenylradical can be substituted up to two times by F, Cl, Br, CF₃, NH₂, CN,OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, COO(C₁-C₆)-alkyl, COO(C₃-C₆)-cycloalkyl, CONH₂,CONH(C₁-C₆)alkyl, or CON[(C₁-C₆)alkyl]₂;  (C₁-C₈)-alkyl, pyrrolidinyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, morpholinyl,tetrahydropyridinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl,wherein each of the rings may be unsubstituted or substituted by phenyl,(C₁-C₆)-alkyl-phenyl, —OH, (C₁-C₈)-alkyl, (C₁-C₆)-alkyl-OH, O-phenyl,S-phenyl, (CO)—(C₁-C₆)-alkyl, or (CO)-phenyl, where the phenylsubstituent is unsubstituted or substituted up to two times by F, Cl,Br, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COOH, COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, CONH(C₃-C₆)cycloalkyl, NH₂, NH—CO—(C₁-C₆)-alkyl, orNH—CO-phenyl; R6 and R7 are, independently of one another, H,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—C(O)—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl-O-phenyl, CHO,CO-phenyl, or  (CH₂)_(n)—Ar, where n can be 0-6, and Ar can be equal tophenyl, biphenylyl, 1- or 2-naphthyl, 1- or 2-tetrahydrofuranyl, 2-, 3-or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-,4- or 5-oxazolyl, 1-pyrazolyl, 3-, 4- or 5-isoxazolyl,(C₃-C₆)-cycloalkyl, piperidinyl, pyrrolidinyl, oxopyridyl, 2- or3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,2-(1,3,5-triazinyl), 2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl,2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl,indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4- or -5-yl and Ar canbe substituted up to two times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—CH₂—O, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, COOH,COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, CONH(C₃-C₆)cycloalkyl, NH₂, NH—CO—(C₁-C₆)-alkyl,NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1 -yl,piperazin-1-yl, 4-methylpiperazin-1-yl, (CH₂)_(n)-phenyl,O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl, or SO₂—(CH₂)_(n)-phenyl, wheren=0-3; or a physiologically acceptable salt thereof.
 2. A compound ofclaim 1, wherein R1, R2 are, independently of one another, NR6R7,pyrrolidinyl, piperidinyl, piperazinyl, or tetrahydropyridyl, whereineach of the rings may be unsubstituted or substituted by phenyl,(C₁-C₆)-alkyl-phenyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-OH, O-phenyl,S-phenyl, (CO)—(C₁-C₆)-alkyl, or (CO)-phenyl, where the phenylsubstituent is unsubstituted or substituted up to two times by F, Cl,Br, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, COOH, COO(C₁-C₆)-alkyl, COO(C₃-C₆)cycloalkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, NH₂, NH—CO—(C₁-C₆)-alkyl, orNH—CO-phenyl; R6, R7 are, independently of one another, H,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-NH—C(O)—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂, or (CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl,biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2-,4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3- or 5-isoxazolyl,(C₃-C₆)-cycloalkyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl,2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl,indol-3-yl, or indol-5-yl and Ar can be substituted up to two times byF, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COOH, COO(C₁-C₆)alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl,NH₂, NH—CO-phenyl, (CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl, orS—(CH₂)_(n)-phenyl, where n=0-3; X, R3 are, independently of oneanother, NR8R9, pyrrolidinyl, piperidinyl, morpholinyl, (C₁-C₈)-alkyl,(CH₂)_(n)-phenyl, where n can be 0-6 and the phenyl radical can besubstituted up to two times by F, Cl, Br, CF₃, CN, OCF₃,O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,COO(C₁-C₆)-alkyl, COO(C₃-C₆)cycloalkyl, CONH₂, CONH(C₁-C₆)alkyl, orCON[(C₁-C₆)alkyl]₂; and R8, R9 are, independently of one another, H,(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl, SO₂-benzyl, SO₂-benzyl-OCH₃, or(CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl orthienyl and Ar can be substituted up to two times by F, Cl, Br, CF₃,NO₂, CN, OCF₃, O—CH₂—O, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,NH—CO-phenyl, (CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl,or SO₂—(CH₂)_(n)-phenyl, where n=0-2.
 3. A compound of claim 1, whereinR1, R2 are, independently of one another, NR6R7, piperidinyl,piperazinyl, or tetrahydropyridyl, wherein each of the rings may beunsubstituted or substituted by phenyl, (C₁-C₆)-alkyl-phenyl,(C₁-C₆)-alkyl, or (CO)—(C₁-C₆)-alkyl; R6, R7 are, independently of oneanother, H, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂, or (CH₂)_(n)—Ar, where n can be 0-6and Ar can be equal to phenyl, 2-, 3- or 4-pyridyl, piperidinyl,pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, or 2-, 3- or 4-morpholinyl and Arcan be substituted up to two times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, COOH, NH₂, or (CH₂)_(n)-phenyl, where ncan be 0-3; X is NR8R9, piperazinyl, (C₁-C₆)-alkyl, or (CH₂)_(n)-phenyl,where n can be 0-6; R3 is NR10R11, or piperazinyl; R8, R9 are,independently of one another, H, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl, SO₂-benzyl,SO₂-benzyl-OCH₃, or (CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equalto phenyl or thienyl; and R10, R11 are, independently of one another, H,(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl, SO₂-benzyl, SO₂-benzyl-OCH₃, or(CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl orthienyl.
 4. A compound of claim 1, wherein R1, R2 are, independently ofone another, NR6R7, piperidinyl, piperazinyl, or tetrahydropyridyl,wherein each of the rings may be unsubstituted or substituted by phenyl,(C₁-C₆)-alkyl-phenyl, (C₁-C₆)-alkyl, or (CO)—(C₁-C₆)-alkyl; R6, R7 are,independently of one another, H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-NH—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-N—[(C₁-C₆)-alkyl]₂, or(CH₂)_(n)—Ar, where n can be 0-6 and Ar can be equal to phenyl, 2-, 3-or 4-pyridyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, or 2-,3- or 4-morpholinyl and Ar can be substituted up to two times by F, Cl,Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, COOH, NH₂,or (CH₂)_(n)-phenyl, where n can be 0-3; X is (C₁-C₆)-alkyl or(CH₂)_(n)-phenyl, where n can be 0-6; R3 is NR10R11 or piperazinyl; andR10, R11 are, independently of one another, H, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO—(C₁-C₆)-alkyl,SO₂-benzyl, SO₂-benzyl-OCH₃, or (CH₂)_(n)—Ar, where n can be 0-6 and Arcan be equal to phenyl or thienyl.
 5. A pharmaceutical composition,comprising one or more compounds of claim 1 and a pharmaceuticallyacceptable carrier.
 6. A method of treating hyperlipidemia, comprisingadministering an effective amount of one or more compounds of claim 1 toa mammal in need of said treatment.
 7. A method of treatingarteriosclerosis, comprising administering an effective amount of one ormore compounds of claim 1 to a mammal in need of said treatment.
 8. Aprocess for preparing a pharmaceutical composition having one or morecompounds of claim 1, which comprises mixing at least one compound ofclaim 1 with a pharmaceutically acceptable excipient and bringing thismixture into a form suitable for administration.
 9. A pharmaceuticalcomposition for treating arteriosclerosis, which comprises an effectiveamount of a compound of claim 1 together with a pharmaceuticallyacceptable carrier.
 10. A process for preparing a compound of claim 1,which comprises reacting, according to the reaction scheme below,

a compound of the formula II, in which X and R3 are as defined underformula I and Hal1 and Hal2 are each a halogen atom, with a compoundR2—H in which R2 is as defined under formula I to give a compound of theformula III and reacting this compound with a compound R1—H in which R1is as defined under formula I to give a compound of the formula I andreacting this compound, if appropriate, with an acid to give apharmacologically acceptable salt thereof.
 11. A method for theprophylaxis of arteriosclerosis, comprising administering an effectiveamount of one or more compounds of claim 1 to a mammal in need of theprophylaxis.
 12. A method for the prophylaxis of a lipid metabolismdisorder, comprising administering an effective amount of one or morecompounds of claim 1 to a mammal in need of the prophylaxis.